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The role of bone in CKD-mediated mineral and vascular disease

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Abstract

Cardiovascular disease is the leading cause of death in pediatric patients with chronic kidney disease (CKD), and vascular calcifications start early in the course of CKD. Based on the growing body of evidence that alterations of bone and mineral metabolism and the therapies designed to treat the skeletal consequences of CKD are linked to cardiovascular calcifications, the Kidney Disease, Improving Global Outcomes (KDIGO) working group redefined renal osteodystrophy as a systemic disorder of mineral and bone metabolism due to CKD, and this newly defined disorder is now known as “chronic kidney disease-mineral bone disorder (CKD-MBD)”. Elevated fibroblast growth factor 23 (FGF23), a bone-derived protein, is the first biochemical abnormality to be associated with CKD-MBD, and high FGF23 levels correlate with increased cardiovascular morbidity and mortality, suggesting that bone is central to both initiating and perpetuating the abnormal mineral metabolism and vascular disease in CKD. The current standard therapies for CKD-MBD affect FGF23 levels differently; non-calcium-based binders with or without concurrent use of dietary phosphate restriction reduce FGF23 levels, while calcium-based binders seem to either increase or have no effect on FGF23 levels. Active vitamin D sterols increase FGF23 levels, whereas therapy with calcimimetics decreases FGF23 levels. Thus, the appropriate therapy that will minimize the rise in FGF23 and prevent cardiovascular morbidity remains to be defined.

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References

  1. Eknoyan G, Lameire N, Barsoum R, Eckardt KU, Levin A, Levin N, Locatelli F, MacLeod A, Vanholder R, Walker R, Wang H (2004) The burden of kidney disease: improving global outcomes. Kidney Int 66:1310–1314

    Article  PubMed  Google Scholar 

  2. U.S. Renal Data System, USRDS (2013) Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2013

  3. Mitsnefes MM (2005) Cardiovascular disease in children with chronic kidney disease. Adv Chronic Kidney Dis 12:397–405

    Article  PubMed  Google Scholar 

  4. Groothoff JW, Lilien MR, van de Kar NC, Wolff ED, Davin JC (2005) Cardiovascular disease as a late complication of end-stage renal disease in children. Pediatr Nephrol 20:374–379

    Article  PubMed  Google Scholar 

  5. Gruppen MP, Groothoff JW, Prins M, van der Wouw P, Offringa M, Bos WJ, Davin JC, Heymans HS (2003) Cardiac disease in young adult patients with end-stage renal disease since childhood: a Dutch cohort study. Kidney Int 63:1058–1065

    Article  PubMed  Google Scholar 

  6. Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112–S119

    Article  CAS  PubMed  Google Scholar 

  7. Parfrey PS, Foley RN (1999) The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10:1606–1615

    CAS  PubMed  Google Scholar 

  8. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J (2006) Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 114:2710–2738

    Article  PubMed  Google Scholar 

  9. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296–1305

    Article  CAS  PubMed  Google Scholar 

  10. Matteucci MC, Chinali M, Rinelli G, Wuhl E, Zurowska A, Charbit M, Pongiglione G, Schaefer F (2013) Change in cardiac geometry and function in CKD children during strict BP control: a randomized study. Clin J Am Soc Nephrol 8:203–210

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Gelev S, Spasovski G, Trajkovski Z, Damjanovski G, Amitov V, Selim G, Dzekova P, Sikole A (2008) Factors associated with various arterial calcifications in haemodialysis patients. Prilozi 29:185–199

    CAS  PubMed  Google Scholar 

  12. Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, Chavkin NW, Rahman M, Wahl P, Amaral AP, Hamano T, Master SR, Nessel L, Chai B, Xie D, Kallem RR, Chen J, Lash JP, Kusek JW, Budoff MJ, Giachelli CM, Wolf M (2013) Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 83:1159–1168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Fang Y, Ginsberg C, Seifert M, Agapova O, Sugatani T, Register TC, Freedman BI, Monier-Faugere MC, Malluche H, Hruska KA (2014) CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol. doi:10.1681/ASN.2013080818

    Google Scholar 

  14. Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK, Chertow GM (2002) Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39:695–701

    Article  PubMed  Google Scholar 

  15. Milliner DS, Zinsmeister AR, Lieberman E, Landing B (1990) Soft tissue calcification in pediatric patients with end-stage renal disease. Kidney Int 38:931–936

    Article  CAS  PubMed  Google Scholar 

  16. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105

    Article  PubMed  Google Scholar 

  17. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483

    Article  CAS  PubMed  Google Scholar 

  18. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    Article  CAS  PubMed  Google Scholar 

  19. Di Lullo L, Floccari F, Santoboni A, Barbera V, Rivera RF, Granata A, Morrone L, Russo D (2013) Progression of cardiac valve calcification and decline of renal function in CKD patients. J Nephrol 26:739–744

    Article  PubMed  Google Scholar 

  20. Ishitani MB, Milliner DS, Kim DY, Bohorquez HE, Heimbach JK, Sheedy PF, Morgenstern BZ, Gloor JM, Murphy JG, McBane RD, Bielak LF, Peyser PA, Stegall MD (2005) Early subclinical coronary artery calcification in young adults who were pediatric kidney transplant recipients. Am J Transplant 5:1689–1693

    Article  PubMed  Google Scholar 

  21. Russo D, Palmiero G, De Blasio AP, Balletta MM, Andreucci VE (2004) Coronary artery calcification in patients with CRF not undergoing dialysis. Am J Kidney Dis 44:1024–1030

    Article  PubMed  Google Scholar 

  22. Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, Presne C, Makdassi R, Andrejak M, Tribouilloy C, Galan P, Safar ME, Choukroun G, Massy Z (2010) Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens 28:163–169

    Article  CAS  PubMed  Google Scholar 

  23. Fang Y, Ginsberg C, Sugatani T, Monier-Faugere MC, Malluche H, Hruska KA (2014) Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int 85:142–150

    Article  CAS  PubMed  Google Scholar 

  24. London GM, Marty C, Marchais SJ, Guerin AP, Metivier F, de Vernejoul MC (2004) Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol 15:1943–1951

    Article  PubMed  Google Scholar 

  25. Damjanovic T, Djuric S, Schlieper G, Markovic N, Dimkovic S, Radojicic Z, Kruger T, Floege J, Dimkovic N (2009) Clinical features of hemodialysis patients with intimal versus medial vascular calcifications. J Nephrol 22:358–366

    CAS  PubMed  Google Scholar 

  26. Barletta GM, Flynn J, Mitsnefes M, Samuels J, Friedman LA, Ng D, Cox C, Poffenbarger T, Warady B, Furth S (2014) Heart rate and blood pressure variability in children with chronic kidney disease: a report from the CKiD study. Pediatr Nephrol 29:1059–1065

    Article  PubMed Central  PubMed  Google Scholar 

  27. Moe SM, Duan D, Doehle BP, O'Neill KD, Chen NX (2003) Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int 63:1003–1011

    Article  CAS  PubMed  Google Scholar 

  28. Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL (2000) Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 87:1055–1062

    Article  CAS  PubMed  Google Scholar 

  29. Wu M, Rementer C, Giachelli CM (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365–373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Shroff RC, McNair R, Skepper JN, Figg N, Schurgers LJ, Deanfield J, Rees L, Shanahan CM (2010) Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 21:103–112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833

    Article  CAS  PubMed  Google Scholar 

  32. Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M, Shlipak MG, Whooley MA, Ix JH (2010) The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 152:640–648

    Article  PubMed Central  PubMed  Google Scholar 

  33. Shroff RC, Donald AE, Hiorns MP, Watson A, Feather S, Milford D, Ellins EA, Storry C, Ridout D, Deanfield J, Rees L (2007) Mineral metabolism and vascular damage in children on dialysis. J Am Soc Nephrol 18:2996–3003

    Article  CAS  PubMed  Google Scholar 

  34. Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, Hiorns M, Donald AE, Deanfield J, Rees L, Shanahan CM (2008) Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118:1748–1757

    Article  CAS  PubMed  Google Scholar 

  35. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81

    Article  CAS  PubMed  Google Scholar 

  36. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953

    Article  CAS  PubMed  Google Scholar 

  37. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617

    Article  CAS  PubMed  Google Scholar 

  38. Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, Young EW, Akizawa T, Akiba T, Pisoni RL, Robinson BM, Port FK (2008) Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 52:519–530

    Article  CAS  PubMed  Google Scholar 

  39. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL (2005) Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16:520–528

    Article  CAS  PubMed  Google Scholar 

  40. Gelev S, Spasovski G, Dzikova S, Trajkovski Z, Damjanovski G, Amitov V, Sikole A (2008) Vascular calcification and atherosclerosis in hemodialysis patients: what can we learn from the routine clinical practice? Int Urol Nephrol 40:763–770

    Article  CAS  PubMed  Google Scholar 

  41. Jean G, Bresson E, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C (2009) Peripheral vascular calcification in long-haemodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant 24:948–955

    Article  CAS  PubMed  Google Scholar 

  42. Li X, Yang HY, Giachelli CM (2006) Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 98:905–912

    Article  CAS  PubMed  Google Scholar 

  43. Shao JS, Cai J, Towler DA (2006) Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423–1430

    Article  CAS  PubMed  Google Scholar 

  44. Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, Schinke T, Karsenty G, Giachelli CM (2001) Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 89:1147–1154

    Article  CAS  PubMed  Google Scholar 

  45. Langman CB, Mazur AT, Baron R, Norman ME (1982) 25-hydroxyvitamin D3 (calcifediol) therapy of juvenile renal osteodystrophy: beneficial effect on linear growth velocity. J Pediatr 100:815–820

    Article  CAS  PubMed  Google Scholar 

  46. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  CAS  PubMed  Google Scholar 

  47. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435

    Article  CAS  PubMed  Google Scholar 

  48. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316:1615–1618

    Article  CAS  PubMed  Google Scholar 

  49. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron RP (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112:683–692

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Wesseling-Perry K, Pereira RC, Tseng CH, Elashoff R, Zaritsky JJ, Yadin O, Sahney S, Gales B, Juppner H, Salusky IB (2012) Early skeletal and biochemical alterations in pediatric chronic kidney disease. Clin J Am Soc Nephrol 7:146–152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Lobao R, Carvalho AB, Cuppari L, Ventura R, Lazaretti-Castro M, Jorgetti V, Vieira JG, Cendoroglo M, Draibe SA (2004) High prevalence of low bone mineral density in pre-dialysis chronic kidney disease patients: bone histomorphometric analysis. Clin Nephrol 62:432–439

    Article  CAS  PubMed  Google Scholar 

  53. van Venrooij NA, Pereira RC, Tintut Y, Fishbein MC, Tumber N, Demer LL, Salusky IB, Wesseling-Perry K (2014) FGF23 protein expression in coronary arteries is associated with impaired kidney function. Nephrol Dial Transplant 29:1525–1532

    Article  PubMed Central  PubMed  Google Scholar 

  54. Lim K, Lu TS, Molostvov G, Lee C, Lam F, Zehnder D, Hsiao LL (2012) Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to FGF-23. Circulation 125:2243–2255

    Article  CAS  PubMed  Google Scholar 

  55. Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N (2005) Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280:2543–2549

    Article  CAS  PubMed  Google Scholar 

  56. Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146:5358–5364

    Article  CAS  PubMed  Google Scholar 

  57. Takasugi S, Akutsu M, Nagata M (2014) Oral phosphorus supplementation secondarily increases circulating fibroblast growth factor 23 levels at least partially via stimulation of parathyroid hormone secretion. J Nutr Sci Vitaminol (Tokyo) 60:140–144

    Article  CAS  Google Scholar 

  58. Hill KM, Martin BR, Wastney ME, McCabe GP, Moe SM, Weaver CM, Peacock M (2013) Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease. Kidney Int 83:959–966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17:1305–1315

    Article  CAS  PubMed  Google Scholar 

  60. Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R (2014) The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol. doi:10.1681/ASN.2013101076

    PubMed  Google Scholar 

  61. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T (2010) PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Ren Physiol 299:F882–F889

    Article  CAS  Google Scholar 

  62. Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE, Bellido T (2011) Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49:636–643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Wan M, Smith C, Shah V, Gullet A, Wells D, Rees L, Shroff R (2013) Fibroblast growth factor 23 and soluble klotho in children with chronic kidney disease. Nephrol Dial Transplant 28:153–161

    Article  CAS  PubMed  Google Scholar 

  64. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, Robling AG, Stayrook KR, Jideonwo V, Magers MJ, Garringer HJ, Vidal R, Chan RJ, Goodwin CB, Hui SL, Peacock M, White KE (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA 108:E1146–E1155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Smith RC, O'Bryan LM, Farrow EG, Summers LJ, Clinkenbeard EL, Roberts JL, Cass TA, Saha J, Broderick C, Ma YL, Zeng QQ, Kharitonenkov A, Wilson JM, Guo Q, Sun H, Allen MR, Burr DB, Breyer MD, White KE (2012) Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest 122:4710–4715

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K (2009) Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45:1161–1168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, Pajevic PD, Wolf M, Juppner H (2013) Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int 84:776–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Portale AA, Wolf M, Juppner H, Messinger S, Kumar J, Wesseling-Perry K, Schwartz GJ, Furth SL, Warady BA, Salusky IB (2013) Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol 9:344–353

    Article  PubMed Central  PubMed  Google Scholar 

  69. Seeherunvong W, Abitbol CL, Chandar J, Rusconi P, Zilleruelo GE, Freundlich M (2012) Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr Nephrol 27:2129–2136

    Article  PubMed  Google Scholar 

  70. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119:2545–2552

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Arnlov J, Carlsson AC, Sundstrom J, Ingelsson E, Larsson A, Lind L, Larsson TE (2013) Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 83:160–166

    Article  PubMed  Google Scholar 

  72. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, Rifkin D, Siscovick DS, Sarnak MJ, Shlipak MG (2012) Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 60:200–207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro OM, Kusek JW, Keane MG, Wolf M (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Mitsnefes MM, Kimball TR, Witt SA, Glascock BJ, Khoury PR, Daniels SR (2003) Left ventricular mass and systolic performance in pediatric patients with chronic renal failure. Circulation 107:864–868

    Article  PubMed  Google Scholar 

  75. Park M, Hsu CY, Li Y, Mishra RK, Keane M, Rosas SE, Dries D, Xie D, Chen J, He J, Anderson A, Go AS, Shlipak MG (2012) Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Nephrol 23:1725–1734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutierrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M (2011) Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. J Am Med Assoc 305:2432–2439

    Article  CAS  Google Scholar 

  77. Srivaths PR, Goldstein SL, Krishnamurthy R, Silverstein DM (2014) High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications. Pediatr Nephrol 29:103–109

    Article  PubMed  Google Scholar 

  78. Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, Bazzano LA, Xie D, Kretzler M, Nessel L, Hamm LL, Negrea L, Leonard MB, Raj D, Wolf M (2012) Fibroblast growth factor 23 and Inflammation in CKD. Clin J Am Soc Nephrol 7:1155–1162

    Article  PubMed Central  PubMed  Google Scholar 

  79. Slatopolsky E, Weerts C, Lopez-Hilker S, Norwood K, Zink M, Windus D, Delmez J (1986) Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 315:157–161

    Article  CAS  PubMed  Google Scholar 

  80. Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, Allison MA, Asplin J, Smits G, Hoofnagle AN, Kooienga L, Thadhani R, Mannstadt M, Wolf M, Chertow GM (2012) Effects of phosphate binders in moderate CKD. J Am Soc Nephrol 23:1407–1415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Jamal SA, Vandermeer B, Raggi P, Mendelssohn DC, Chatterley T, Dorgan M, Lok CE, Fitchett D, Tsuyuki RT (2013) Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 382:1268–1277

    Article  CAS  PubMed  Google Scholar 

  82. Oliveira RB, Cancela AL, Graciolli FG, dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moyses RM (2010) Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 5:286–291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Gonzalez-Parra E, Gonzalez-Casaus ML, Galan A, Martinez-Calero A, Navas V, Rodriguez M, Ortiz A (2011) Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients. Nephrol Dial Transplant 26:2567–2571

    Article  CAS  PubMed  Google Scholar 

  84. Isakova T, Gutierrez OM, Smith K, Epstein M, Keating LK, Juppner H, Wolf M (2011) Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease. Nephrol Dial Transplant 26:584–591

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Yokoyama K, Hirakata H, Akiba T, Fukagawa M, Nakayama M, Sawada K, Kumagai Y, Block GA (2014) Ferric citrate hydrate for the treatment of hyperphosphatemia in nondialysis-dependent CKD. Clin J Am Soc Nephrol 9:543–552

    Article  PubMed Central  PubMed  Google Scholar 

  86. Baker LR, Muir JW, Sharman VL, Abrams SM, Greenwood RN, Cattell WR, Goodwin FJ, Marsh FP, Adami S, Hately W (1986) Controlled trial of calcitriol in hemodialysis patients. Clin Nephrol 26:185–191

    CAS  PubMed  Google Scholar 

  87. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R (2003) Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349:446–456

    Article  CAS  PubMed  Google Scholar 

  88. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, Thadhani R (2005) Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 16:1115–1125

    Article  CAS  PubMed  Google Scholar 

  89. Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP, Kilpatrick RD, Shinaberger CS, McAllister CJ, Budoff MJ, Salusky IB, Kopple JD (2006) Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 70:771–780

    Article  CAS  PubMed  Google Scholar 

  90. Naves-Diaz M, Alvarez-Hernandez D, Passlick-Deetjen J, Guinsburg A, Marelli C, Rodriguez-Puyol D, Cannata-Andia JB (2008) Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int 74:1070–1078

    Article  CAS  PubMed  Google Scholar 

  91. Tentori F, Albert JM, Young EW, Blayney MJ, Robinson BM, Pisoni RL, Akiba T, Greenwood RN, Kimata N, Levin NW, Piera LM, Saran R, Wolfe RA, Port FK (2008) The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 24:963–972

    Article  PubMed  Google Scholar 

  92. Tentori F, Hunt WC, Stidley CA, Rohrscheib MR, Bedrick EJ, Meyer KB, Johnson HK, Zager PG (2006) Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 70:1858–1865

    Article  CAS  PubMed  Google Scholar 

  93. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K (2008) Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med 168:397–403

    Article  CAS  PubMed  Google Scholar 

  94. Wesseling-Perry K, Pereira RC, Sahney S, Gales B, Wang HJ, Elashoff R, Juppner H, Salusky IB (2010) Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney Int 79:112–119

    Article  PubMed  Google Scholar 

  95. Ito I, Waku T, Aoki M, Abe R, Nagai Y, Watanabe T, Nakajima Y, Ohkido I, Yokoyama K, Miyachi H, Shimizu T, Murayama A, Kishimoto H, Nagasawa K, Yanagisawa J (2013) A nonclassical vitamin D receptor pathway suppresses renal fibrosis. J Clin Invest 123:4579–4594

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Alam MU, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M, Vizard TN, Sage AP, Martin D, Ward DT, Alexander MY, Riccardi D, Canfield AE (2009) Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res 81:260–268

    Article  CAS  PubMed  Google Scholar 

  97. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM (2005) Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int 68:1793–1800

    Article  CAS  PubMed  Google Scholar 

  98. Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K, Moustafa M, Goodman WG, Lopez N, Downey G, Dehmel B, Floege J (2011) The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 26:1327–1339

    Article  CAS  PubMed  Google Scholar 

  99. Chertow GM, Block GA, Correa-Rotter R, Drueke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS (2012) Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 367:2482–2494

    Article  CAS  PubMed  Google Scholar 

  100. Kim HJ, Kim H, Shin N, Na KY, Kim YL, Kim D, Chang JH, Song YR, Hwang YH, Kim YS, Ahn C, Lee J, Oh KH (2013) Cinacalcet lowering of serum fibroblast growth factor-23 concentration may be independent from serum Ca, P, PTH and dose of active vitamin D in peritoneal dialysis patients: a randomized controlled study. BMC Nephrol 14:112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by USPHS grants DK67563 (IBS), DK35423 (IBS), DK 80984 (KW-P), by CTSI grant UL1TR000124 (IBS) and funds from the Casey Lee Ball Foundation (IBS and KW-P).

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Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, CA, USA

    Nadine M. Khouzam, Katherine Wesseling-Perry & Isidro B. Salusky

  2. A2-383 MDCC, 650 Charles Young Dr, Los Angeles, CA, 90095, USA

    Isidro B. Salusky

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  1. Nadine M. Khouzam
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  2. Katherine Wesseling-Perry
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  3. Isidro B. Salusky
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Correspondence to Isidro B. Salusky.

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Khouzam, N.M., Wesseling-Perry, K. & Salusky, I.B. The role of bone in CKD-mediated mineral and vascular disease. Pediatr Nephrol 30, 1379–1388 (2015). https://doi.org/10.1007/s00467-014-2919-z

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  • DOI: https://doi.org/10.1007/s00467-014-2919-z

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